This 4 year PhD studentship offered in Dr Amaya Virós’s research group is based at the Cancer Research UK Manchester Institute, Alderley Park, Cheshire
Elderly cutaneous melanoma patients with stage IV disease are able to build strong responses to immunotherapy checkpoint inhibitors (IT), and in some instances the response is greater than in stage-matched younger patients. Recently, a lower intratumour heterogeneity (ITH) has been linked to better IT response, greater T cell infiltration of the tumour, lower immune-suppressive TME enveloping the melanoma, and to a better prediction of IT response in both mouse and human patients, independently of tumour mutation burden (Samuels, Cell, Sept 2019). However, there is contrasting preliminary data describing how young mice with melanomas established from cell lines following exposure to a high-ultraviolet light B (UVB) radiation, leading to a higher tumour mutation burden (“high”-TMB) are more likely to respond to immunotherapv compared to young mice with melanoma established from a low tumour mutation burden melanoma cell line (“low”-TMB melanomas). Moreover, in our recent work we have found a genetic signature that correlates with IT response in the elderly (under review).
Critically, there are ongoing experiments re-challenging mice that have responded to anti-PD1 with different subtypes of melanomas to examine the tumour versus host factors that explain sustained responses. Importantly, healthy aged skin retains T cells and could harbour a higher number of T memory regulatory T cells (TRM) than young skin. One question is if the TRM population in aged skin has sufficient T cell receptor (TCR) heterogeneity, compared to peripheral blood, to mount a local response to melanoma re-challenges. T cells are now proven to be highly mobile within young human epidermis and to travel from the epidermis to the dermis traversing the basement membrane (Schumacher, Nature Immunology 2019).
Aims of the project
The strong response to immunotherapy in aged melanoma patients could be due to tumour-specific effects characteristic of old age melanoma: tumour cells bearing a higher neoantigen load; tumour cells having a distinct clonal/subclonal heterogeneity pattern; aged human tumours and matching peripheral skin presenting greater numbers of TRM in the tumour and skin with conserved or increased TCR heterogeneity over a lifetime, and preserved T cell motility.
In this project, we aim to dissect the melanoma tumour-specific characteristics driving responses in aged versus young melanoma in vivo. We are interested in examining the genetic factors, including TMB, ITH and specific mutations from our preliminary data in mounting a response in the aged and young population. We will investigate if immune responses, after re-challenging “responders” to different genetic tumour subtypes, correlate with age.
We will model the distinct pathphysiological tumour types using in vivo models of aged and young animals, immune deficient and T cell deficient animals to dissect the relevant pathways driving response and sustained responses in the elderly. We will additionally use bioinformatics to investigate the relationship between age, specific mutations, ITH, adaptive immune cell populations, cytolytic score, in our in vivo models and in humans.
This work will dissect the factors underpinning response to IT in the aged population. Understanding the variability in IT response by age will help inform future therapies.
Applications are invited from exceptionally high calibre students, graduates or final year undergraduates who should hold or are expected to gain a first/upper second-class honours degree in a relevant subject as part of a University degree course.
Applicants can find full group project details, entry criteria and details on how to apply online at: http://www.cruk.manchester.ac.uk/education/PhD-Studentships
Closing date: Friday 3 January 2020 – 2100 hours GMT
Interview date: Tuesday 18 February 2020, Alderley Park, Cheshire